DESCRIPTION (From the Applicant?s Abstract): The incidence of abnormalities in early development of the inner ear is approximately 1 in 500, 50 percent of which are genetic in origin. These structural abnormalities include cochlear and vestibular dysplasias which are frequently diagnosed due to sensorineural hearing loss. However, the precise developmental defect in the overwhelming number of individuals diagnosed with sensorineural hearing loss is unknown. The objective of this research is to characterize the role of fgf-l9 in early inner ear development and to determine how this molecular protagonist acts in the initial cell-fate specification of the ear. As the function of genes at this time point in development are determined, their potential role in human diseases with ear abnormalities can be analyzed. The early development of the ear occurs in three phases: formation of the otic placode; morphogenesis of the otic placode, generating the otic cup and otocyst; and regional patterning of the otocyst. The experiments outlined here will isolate mouse fgf-19 and characterize its role in early ear development. Initial studies of fgf-l9 in the chick suggest it is located in the right time and place to play a role in early otic induction. Mouse fgf-19 will be isolated and characterized using degenerate PCR, library screening and in situ hybridization. The function of mouse fgf-19 will be determined by the generation and analysis of a null mutant using gene targeting. The potential role of fgf-l9 in a developmental cascade involving fgf-3 or fgf-10 will be studied by examining the expression of these genes in the fgf-l9 mutant mice.